9alpha-halo-11alpha-alkyl-11beta-hydroxy steriods of the androstane series and intermediates therefor



This invention relates to the synthesis of steroids and has for itsobject the provision of a new class of physiologically active steroids,which may be represented by the formula wherein R is lower alkyl(preferably methyl), R is hydrogen or lower alkyl (preferably methyl), Ris hydroxy or acyloxy (particularly the acyloxy radical of a hydrocarboncarboxylic acid having less than ten carbon atoms), or together R and R"is keto, and X is a halogen of atomic number greater than nine (i.e.iodine, bromine and particularly chlorine). These new steroids arephysiologically active substances which possess androgenie activity.Hence the steroids of this invention can be used in lieu of knownandrogenic steroids, such as methyl testosterone, in the treatment ofmenopausal disturbances, being formulated for such administration in thesame type of peroral preparations as methyltestosterone, for example,with concentration, and/or dosage based on the activity of theparticular compound.

The new steroids of this invention are prepared by interacting9a-fiuoro-1l-ketotestosterone, a 17-ester thereof, or9u-fluoro-l7oc-1ower alkyl-ll-ketotestosterone (e.g.,9afluoro-l7a-methyl 11 ketotestosterone) with pyrrolidine to yield thecorresponding 3-pyrrolidino-A androstadiene derivative of the generalformula nited States Patent 0 wherein A is hydrogen or lower alkyl, andBis hydroxy' or acyloxy, which are new intermediates of thisinvention.The reaction is preferably conducted in an inert organic solvent for thesteroid reactant (e.g. methanol) atan elevated temperature, such as thereflux temperature of the solvent. 7

The S-pyrrolidino steroids are then interacted with a lithium loweralkyl (e.g. lithium methyl and lithium ethyl), followed by hydrolysis ofthe 3-pyrro1idino group in situ, preferably with a buflier consisting ofsodium acetate-acetic acid, thereby yielding the new 913,116- epoxideintermediates of this invention, having the general formula A on whereinA and'Rare as hereinbefore defined. p I

The epoxides are then reacted with a hydrogen halide, wherein thehalogen has an atomic number greater than nine, to yield compounds ofthe first formula givenhereinbefore wherein R is hydroxy.

If a 17-ester is desired, the free 17-hydroxy compound can be acylatedin the usual manner as by treatment with an acyl halide or acidanhydnide of the desired acid. Particularly preferred are the acylchlorides and acidane hydrides of hydrocarbon carboxylic acids havingless than ten carbon atoms, as exemplified by the lower alkanoic acids(e.g., acetic, propionic and enanthic acid), the monocyclic aromaticcarboxylic acids (e.g. benzoic and toluic acid), the monocyclicaralkanoic acids (e.g. phenacetic and B-phenylpropionic acid), the loweralkenoic acids, the cyeloalkane carboxylic acids, and the cycloallrenecarboxylic acids. The acylation is preferably conducted in the presenceof an organic base, such as pyridine.

Ifa l7-keto steroids is desired and R is hydrogen, the free 17fi-hydroxysteroid can be oxidized in the usual manner, as by treatment withchromium trioxide in aqueous sulfuric acid to convert the 17fl-hydro'xy'radical to a 17-keto derivative.

'The process of this invention can be illustrated by the followingschematic analysis employing 9u-fluoro-1 1- ketotes-tosterone,9a-fluoro-1l-ketotestosterone 17-acetate, and 9a-fluoro-17-methy1 11ketotestosterone as starting materials:

Patented Sept. 26, IQGI The following examples are illustrative of theinvention (all temperatures being in centigrade):

EXAMPLE 1 3-pyrrolidino-9a-fluoro-17armethyl A -andr0stadiene-17B-ol-11-0ne (IV) To a refluxing solution of 983 mg. of 9u-fluoro-11-keto-l7a-methyltestosterone (I) [prepared by the method disclosed byHerr et al., J. American Chemical Society, 78, 500 (1956)] in 10 ml. ofmethanol under nitrogen is added 1 ml. of redistilled pyrrolidine.Heating is continucd for two minutes during which time crystals separatefrom solution. The crystals are collected, washed with a little coldmethanol and dried in vacuo. About 1.01 g, of the 3-pyrrolidino compound(IV) is obtained, having a melting point of about 195-202 (dec.)';

A223,? 3.05 (broad), 5.78, 6.07, 6.20;

EXAMPLE 2 (a). Preparation of 9a-fluoro-1I-ketotestosterone (II) and9a-fluaro-1Ifl-hydroxytestosterone.-A solution of 3. g. of9a-fluoro-1l-keto-androstenedione in 200 ml. of methanol is stirred with215 mg. of sodium borohydride at 0 for 1 hour. After acidifying thesolution with a few drops of glacial acetic acid, it is concentrated tohalf its volume, diluted with water and the steroids extracted withchloroform. The chloroform is washed with water, dried over sodiumsulfate and the solvent removed. in vacuo.. The residue is; triturated.with 50 ml. of benzene. The insoluble maten'al is collected andcrystallized from acetone-hexane to give about 790 mg. of9a-fluoro-1lflhydroxytestosterone having M.P. about 224-230.Crystallization from acetone-hexane yields an analytical sample havingM.P. about 232233; [121 +133 (c. 1.04 in OHCl V A35, 239m (17,300); k

max.

Analysis.-Calcd. for C H O F (322.41): C, 70.77; H, 8.44; F, 5.89.Found: C, 71.27; H, 8.04; F, 5.89.

The benzene filtrate described above is absorbed on 100 g. ofacid-washed alumina. Elution with chloroform (800 ml.) followed bycrystallization from acetonehexane gives about 780- mg. of9a-fiuoro-ll-ketotestosterone (II), M.P. about l49-'152. Crystallizationfrom A332,, 234mg (16,200); N 2.85, 2.92, 5.78, 5.97 6.12;;

max.

Analysis.Calcd. for C H O F (320.40); C, 71.22; H, 7.87; F, 5.93. Found:C, 71.50; H, 7.76; F, 6.09.

Elution of the column with chloroform-acetone (1:1, 500 ml.) followed bycrystallization from acetone-hexane yields about 200 mg. of the1'l/3-hydroxy compound, M.P. 228-232".

(b) Preparation of 3-pyrr0lidin0-9a-fluoro-A-andr0stadiene-17fl-0l-11-0ne (V).-T0 a refluxing solution of 450 mg. of9a-fluoro-1l-ketotestosterone (II) in 4 ml. of methanol under nitrogenis added 0.4 ml. of redistilled pyrrolidine and heating is continued fortwo minutes during which time the 3-pyrrolidino compound (V) separatesfrom solution. The crystals are collected, washed with a little ice-coldmethanol and dried in vacuo. About 456 mg. of3'pYII'OHdmO-90t-fll1OI'OrA -3.l1dIOS" tadiene17 3-o1-11-one is obtainedhaving a M.P. of about 125-135" (dec.);

EXAMPLE 3 (:1) Preparation of 9a-flu0ro-1I-ketotestosterone 17flacetate(III).-A solution of 1.15 g. of 9u-fluoro-11/3- 'hydroxytestosterone(prepared in Example 2, section a) in 10 ml. of pyridine and 3 ml. ofacetic anhydride is heated at for one hour. The mixture is diluted withwater and the steroids extracted with chloroform, the chloroform extractthen being washed with water and dilute hydrochloric acid, dried oversodium sulfate and evaporated to dryness in vacuo. Two crystallizationsfrom methanol give about 510 mg. of 9a-fluoro-11flhydroxytestosteronel7fl-acetate, M.P. about 193-495; [12],, (c. 0.96 in CHCl A311,, 239m(15,400); k211i? 2.85, 2.94, 5.77, 5.87, 5.95, 6.06 Riff 2.90, 5.78,6.00, 6.16 0

Analysis.-Calcd. for C H 0 F (364.44): C, 69.21; H, 8.02; F, 5.21.Found: C, 69.49; H, 8.16; F, 5.07.

A solution of 400 mg. of 9a-fluoro-llp-hydroxytestosterone 17,6-acetatein 7 ml. of acetone is stirred with 5 ml. of chromium trioxide in 0.67 Nsulfuric acid (200 mg./ml.) for 30 minutes. The solution is then dilutedwith water, the precipitated solid collected and crystallized fromacetone-hexane. The resulting 9zz-fillOI'O-11-k6t0- testosterone17fi-acetate (1H) (about'270 mg.) has M.P. about 234-235"; [th, -]-'117(c. 1.39 in CHCI xgg, 23401,. (16,100); W 2.80, 5.80, 0.03, 6.20,

EXAMPLE 4 9 3,1 1 B-l-epoxy-II u,I7a-dimethyltestosterone (VII) 1.01 g.of 3-pyrrolidino-90t-fluoro-17a-methyl-A androstadiene-l7 8-ol-ll-one inml. of benzene is stirred under nitrogen with 10 ml. of an etherealsolution of lithium methyl (14.1 mg./m-l.) for two hours. The solutionis then cooled and 25 m1. of acetate bufifer (comprising of 20 ml. ofmethanol, 2 ml. of methanol, 2 ml. of water, 1.6 ml. acetic acid and 1.6g. of sodium acetate) is cautiously added, the reaction mixture thenbeing re fluxed for three hours. The mixture is diluted with water, andthe steroids extracted with chloroform. The chloroform extract is washedwith water, dried over sodium sulfate and the solvent removed in vacuo.The crystalline residue (about 716 mg.) so obtained has a melting pointof about 246-248". Crystallization of a sample from chloroform-methanolyields 9,8,llfl-oxido- 1la,l7a-dimethyltestosterone with M.P. about249-250; [04] 24 (c. 1.33 in CHCl Analysis.--Calcd. for C H O (330.45);C, 75.87; H, 9.25. Found: C, 76.32; H, 9.15.

EXAMPLE 5 I1 a-methyl-9/3J 1,8-epoxy testosterone (VIII) 456 mg. of3-pyrrolidino-9afluoro-A -androstadiene- 17 8-ol-11-one in l 5 ml. ofbenzene is stirred under nitrogen with 10 ml. of an ethereal solution oflithium metal (10 mg. lithium/ml.) for 3.5 hours. The solution is thencooled and 25 ml. of acetate buffer (comprising of 20 ml.-of methanol, 2ml. of Water, 1.6 ml. of acetic acid and 1.6 g. of sodium acetate) iscautiously added, the reaction mixture then being refluxed for 3 hours.The mixture is diluted with Water, and the steroids extracted withchloroform. The chloroform is washed with Water, dried over sodiumsulfate and the solvent removed in vacuo. Crystallization fromacetone-hexane gives about 140 mg. of11a-methyl-9B,11/3-oxidotestosterone (VHI) having M.P. about 198-203";[a] 6.5 (c. 1.03 in CHCl A313 244m (17,000); Afigi? 2.91, 6.06, 6.21

Analysis.Calcd. for C H O (316.42): C, 75.91; H, 8.92. Found: C, 76.10;H, 8.56.

The mother liquors from the above crystallization are evaporated todryness in vacuo, the residue is dissolved in 25 ml. of benzene andabsorbed on 6 g. of acid-washed alumina. Elution with chloroform-benzene(1:19, 300 ml.), followed by, crystallization from acetone-hexane givesabout 70 mg. of the oxido compound (VIII) having M.P. about 195203.

EXAMPLE 6 11 a-methyl-QBJ 1 fi-epoxytestosterone (VIII) 45 mg. of3-pyrrolidino-9a-fluoro-A -androstadiene- 17B-o1-11-one 17,8-acetate in10 ml. of benzene is stirred under nitrogen with 10 ml. of ethereallithium methyl mg. Li/ml.) for 3 /2 hours. The reaction mixture is thenhydrolyzed with 25 mliof acetate buifer as described in Example 5, andthe steroids are isolated withchloroform. The chloroform solutioniswashe'd with water, dried over sodium sulfate and evaporated in vacuo.The residue is dissolved in 2 ml. of benzene and absorbed on 9 g. ofacid-washed alumina. Elution with chloroformbenzene (1:19,30.0.m1.;.1:9, 200 ml), followed by crystallization from acetone-hexane.gives about 50 mg. of 11oc-methyl-9fi,-1lfi-epoxytestosterone havingM.P. about 200-203. The identity of this material with that described inExample 5 is confirmed by mixture determination and infrared comparison.

EXAMPLE 7 9u-chl0r0-I 1 B-hydroxy-I 0a,] 7ix-dimethyltestosterone (IX) iA solution of 50 mg. of 9,8,1lp-oxido 1la,l70t-dimethyltestosterone in 5ml. of chloroform is treated with 2 ml. of 0.5 N hydrogen chloride inchloroform. The solution is allowed to stand at 0 for four hours and isthen neutralizedby the addition of aqueous sodium bicarbonate. Morechloroform (20 ml.) is added and the reaction mixture is washed severaltimes with water, dried over sodium sulfate and the solvent removedunder reduced pressure. Crystallization of the residue fromacetone-hexane yields about 41.6 mg. of the chloro-hydrin (IX), M.P.about 253-255 (dec.); [u] +132.2 (c. 0.8 in OHCl Analysis.-Calcd. for CH O Cl (366.91): C, 68.71; H, 8.52; Cl, 9.66. Found: C, 68.40; H, 8.44;Cl, 9.38.

Similarly, by substituting hydrogen bromide or hydrogen iodide in theprocedure of Example 7, 9a-br0m0-11B-hydroxy-l1u,l7a-dimethyltestosterone and 9a-iodo-l1,8- hydroxy-l1a,17-dimethy1testosterone are formed, respectively;

EXAMPLE 8 9a-chl0r0-1 1 fl-hydroxy-I I a-methyltestosterone (X)Following the procedure of Example 7 but substituting 50 mg. of1la-methyl-9B,llfl-epoxytestosterone for the epoxide reactant in theexample, there is obtained 9wchloro-l lfi-hydIoxy-llot-methyltestosterone.

Similarly, by substituting hydrogen bromide and hydrogen iodide thet-bI'OIIlO and 9a-iodo derivatives are formed respectively.

EXAMPLE 9 9a-chl0ro-I1B-hydroxy-11 a-methyltestostrone 17B-acetate (XI)EXAMPLE 10 9a-chlor0-11a-methyl-A -andr0stene-1113-0l-17-0ne (XII) To asolution of 50 mg. of 9a-chloro-11/8-hydroxy-11umethyltestosterone (X)in 10 ml. of acetone is added with stirring suflicient chromium trioxidein 0.67 H. sulfuric acid (200 mg./ml.) to give a permanent browncoloration. After stirring the mixture at room temperature for 30minutes, water is added. The steroids are extracted with chloroform, thechloroform extract then being washed with water, dried over sodiumsulfate and evaporated to dryness in vacuo. Crystallization fromacetone- 7 hexane gives a pure sample of 9achloro-11oc-methyl-Aandrostene-l 1 3-01-17 -one (XII) The invention may be otherwisevariously embodied within the scope of the appended claims.

What is claimed is: 1. IA steroid of the general formula wherein R islower alkyl.

5. 95,1 1 B-epoxy-l 1a-methyltestosterone 6. A process for preparing asteroid of the general formula A OH wherein R is lower alkyl and A isselected from the group consisting of hydrogen and lower alkyl, and X isa halogen of atomic number greater than nine, which com- 8 prisesinteracting the corresponding steroid of the general formula wherein Rand A are as above defined, with a hydrogen halide wherein the halogenhas an atomic number greater than nine.

7. A process for preparing a steroid of the general formula wherein A isselected from the group consisting of hydrogen and lower alkyl and R islower alkyl, which comprises interacting a steroid of the generalformula wherein A and R are as above defined and B is selected from thegroup consisting of hydroxy and the acyloxy radical of a hydrocarboncarboxylic acid having less than ten carbon atoms, with lithium loweralkyl in an aqueous medium and treating the product formed with ahydrolyzing agent.

References Cited in the file of this patent UNITED STATES PATENTS2,793,218 Herr May 21, 1957 2,816,121 Gould et al Dec. 10, 1957 .2,837,517 Herr June 3, 1958

4. A STEROID OF THE GENERAL FORMULA